1. Field of the Invention
This invention relates to the use of certain 3-substituted-2-oxindole derivatives and the pharmaceutically-acceptable base salts thereof to inhibit interleukin-1 biosynthesis in a mammal. This invention also relates to the use of such compounds for treating interleukin-1 mediated disorders and dysfunctions such as bone and connective tissue metabolism disorders and immune dysfunction in a mammal. The methods of this invention comprise administering an effective amount of the compounds and salts of this invention to such a mammal.
2. General Background
Certain 3-substituted-2-oxindole-1-carboxamides of the formula ##STR1## and the pharmaceutically-acceptable base salts thereof wherein, inter alia, X and Y are each H, F, Cl, Br or CF.sub.3 ; and R.sup.1 is --(CH.sub.2).sub.2 --Q--R.degree. where n is zero, Q is a divalent radical derived from a compound selected from the group consisting of, inter alia, furan, thiophene, thiazole, oxazole and isoxazole and R.degree. is H or (C.sub.1 -C.sub.3)-alkyl are disclosed in U.S. Pat. No. 4,556,672 which is assigned to the assignee hereof. That patent discloses that those compounds, in addition to being useful as antiinflammatory and analgesic agents, are inhibitors of both the cyclooxygenase (CO) and lipoxygenase (LO) enzymes. The teachings thereof are incorporated herein by reference.
Certain 3-substituted-2-oxindole derivatives of the formula ##STR2## and the pharmaceutically-acceptable base salts thereof wherein, inter alia, X and Y are each H, F, Cl, Br or CF.sub.3 ; and R.sup.1 is --(CH.sub.2).sub.n --Q--R.degree. where n is zero, Q is a divalent radical derived from furan, thiophene, thiazole, oxazole or isoxazole and R.degree. is H or (C.sub.1 -C.sub.3)alkyl; and R.sup.2 is (C.sub.1 -C.sub.6)alkyl are disclosed in U.S. Pat. No. 4,569,942 which is assigned to the assignee hereof. That patent discloses that those compounds, in addition to being useful as antiinflammatory and analgesic agents, are inhibitors of both the cyclooxygenase (CO) and lipoxygenase (LO) enzymes. The teachings thereof are incorporated herein by reference.
U.S. patent applications Ser. No. 340,113, filed Apr. 18, 1989 and Ser. No. 473,266, filed Jan. 31, 1990, both of which are assigned to the assignee hereof, disclose certain 3-substituted-2-oxindole compounds of the formula ##STR3## and the pharmaceutically-acceptable base salts thereof wherein, inter alia, X and Y are each H, F, Cl, Br or CF.sub.3 ; R.sup.1 is H; R.sup.2 is CONR.sup.7 R.sup.8 wherein R.sup.7 is H and R.sup.8 is H or (C.sub.1 -C.sub.6)alkyl; Q is ##STR4## where Q.sup.1 is ##STR5## W is O or S, A and B are various substituents provided A and B cannot both be H nor A be H and B be (C.sub.1 -C.sub.4)alkyl; and the tautomeric form thereof as a ketone. That application discloses that those compounds are useful as inhibitors of prostaglandin H.sub.2 synthase and interleukin-1 biosynthesis, per se, and as analgesic, antiinflammatory and antiarthritic agents in the treatment of chronic antiinflammatory diseases.
U.S. Pat. No. 4,861,794, assigned to the assignee hereof, discloses the use of compounds of the formula ##STR6## and the pharmaceutically-acceptable base salts thereof wherein X is H, Cl or F; Y is H or Cl; and R is benzyl or thienyl to inhibit biosynthesis of interleukin-1 (IL-1) and to treat IL-1 mediated disorders and dysfunctions.
Interleukin-1 (IL-1) has been reported to stimulate bone resorption both in vitro and in vivo. Hayward, M. and Fiedler-Nagy, Ch., Agents and Actions, 22, 251-254 (1987). It is also reported therein that IL-1, inter alia, induces the production of prostaglandin E.sub.2 (PGE.sub.2). PGE.sub.2 is a stimulator of bone resorption and has been implicated in bone loss. Hayward, M. A. and Caggiano, T. J., Annual Reports in Medicinal Chemistry, 22, Sect. IV, Chapter 17, 172-177 (1987). Osteoporosis is defined as a debilitory loss of bone mineral which results in higher fracture rates. See Hayward, M. A. and Caggiano, T. J., supra, and references cited therein.
Interleukin-1 has been reported to be involved in the pathogenesis of many diseases. See Dinarello, C. A., J. Clin. Immunol., 5, 287-297 (1985), the teachings of which are incorporated herein by reference. Further still, elevated levels of IL-1 like material have been found to be associated with psoriasis. Camp, R. D., et al., J. Immunol., 137, 3469-3474 (1986).
The non-steroidal antiinflammatory agent etodolac, 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]-indole-1-acetic acid, has been disclosed in U.S. Pat. No. 4,677,132 to lower PGE.sub.2 and reduce bone resorption. Etodolac has the formula ##STR7##
It has been reported that therapeutic levels of nonsteroidal antiinflammatory agents such as indomethacin and ibuprofen do not reduce IL-1 production. Similarly, cyclosporine A had no such effect. Corticosteroids, however, are effective in reducing IL-1 production. Dinarello, C. A., supra. Certain lipoxygenase inhibitors such as 5,8,11,14-eicosatetraynoic acid (ETYA) and 3-amino-1,3-trifluoromethylphenyl-2-pyrazoline (BW755C) have been reported to decrease in vitro production of leukocytic pyrogen (putative IL-1) from human monocytes. Dinarello, C. A., et al., Int. J. Immunopharmac., 6, 43-50 (1984).
However, until the invention herein, there was no report of use or intent to use the compounds or salts of this invention to inhibit IL-1 biosynthesis independent of lipoxygenase inhibition and to treat IL-1 mediated disorders and dysfunctions such as certain bone and connective tissue metabolism disorders and certain immune dysfunctions with such compounds nor any appreciation of their role in such treatments.